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Pharmaceutical Industry: Manufacturing Process Improvement

Capability

Regulatory, Compliance & Quality
Technical Services

Client

A major US generic pharmaceutical company

Problem

The client had filed an ANDA for an extended release product that represented a significant sales opportunity exceeding $100M annually. The client believed they were the first to file and, therefore, would have a six-month exclusive sales opportunity in the generic market once they received FDA approval. The client’s process development group could not produce successful batches in intermediate equipment, despite numerous attempts and their experience with several other controlled-release products. Since time was limited, there was no opportunity to modify the process as filed with the FDA. The complex process included three fluid bed coating steps: blending, compression, and final pan coating.

Approach

Tunnell experts, including a formulation subject matter expert, a process engineer, a statistician, a data analyst, and a project manager, formed a team with the client and experts from the equipment manufacturer to develop a commercial process. The Tunnell team provided scientific expertise, process engineering support, experimental protocol development, and data analysis – including statistical modeling support and project strategic scheduling. The team analyzed all available data, executed experiments to better understand the polymer coating, performed scouting experiments to assess various operating parameter values, and then designed two sets of experiments at a small scale. These experiments were the basis for statistical models that helped the team understand the interaction of the operating parameters and raw materials in the process. This information was used to scale the processes to the commercial scale fluid bed machines. Studies were carried out to determine optimal blending times. A series of designed experiments for compression were executed to determine the correct balance among turret speed, feeder speed, compression force to meet thickness, hardness, and content uniformity specifications.

Results

The team found that dissolution results of the third coating step were affected by the particle size of the starting material in the first step. Through detailed data analysis, the team was able to develop a process that could accommodate varying particle size starting material and still meet the dissolution requirements. Process understanding was dramatically increased. Statistical modeling showed the critical operating parameters and the limits that should be set for each of them. The use of a DoE for compression enabled the team to meet the specifications for hardness and thickness, which would have been difficult to do had the client followed their usual method of determining acceptable press conditions.

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